Development of a Humanized Antibody with High Therapeutic Potential against Dengue Virus Type 2 英文参考文献.docVIP

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Development of a Humanized Antibody with High Therapeutic Potential against Dengue Virus Type 2 英文参考文献.doc

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Development of a Humanized Antibody with High Therapeutic Potential against Dengue Virus Type 2 英文参考文献

DevelopmentofaHumanizedAntibodywithHigh TherapeuticPotentialagainstDengueVirusType2 Pi-ChunLi1,2,Mei-YingLiao2,Ping-ChangCheng2,Jian-JongLiang3,I-JuLiu2,Chien-YuChiu2, Yi-LingLin3,Gwong-JenJ.Chang4,Han-ChungWu1,2* 1Graduate Institute of LifeSciences,National Defense Medical Center,Taipei,Taiwan, 2Institute ofCellular andOrganismicBiology, Academia Sinica, Taipei, Taiwan, 3InstituteofBiomedicalSciences,AcademiaSinica,Taipei,Taiwan,4ArbovirusDiseasesBranch,DivisionofVector-BorneInfectiousDiseases,CentersforDiseaseControl andPrevention,PublicHealthService,UnitedStatesDepartmentofHealthandHumanServices,FortCollins,Colorado,UnitedStatesofAmerica Abstract Background:Denguevirus(DENV)isasignificantpublichealththreatintropicalandsubtropicalregionsoftheworld.A therapeuticantibodyagainsttheviralenvelope(E)proteinrepresentsapromisingimmunotherapyfordiseasecontrol. Methodology/Principal Findings: We generated seventeen novel mouse monoclonal antibodies (mAbs) with high reactivityagainstEproteinofdenguevirustype2(DENV-2).ThemAbswerefurtherdissectedusingrecombinantEprotein domainI-II(E-DI-II)andIII(E-DIII)ofDENV-2.Usingplaquereductionneutralizationtest(PRNT)andmouseprotectionassay withlethaldosesofDENV-2,weidentifiedfourserotype-specificmAbsthathadhighneutralizingactivityagainstDENV-2 infection.Ofthefour,E-DIIItargetingmAbDB32-6wasthestrongestneutralizingmAbagainstdiverseDENV-2strains.Using phage display and virus-like particles (VLPs) we found that residue K310 in the E-DIII A-strand was key to mAb DB32-6 binding E-DIII. We successfully converted DB32-6 to ahumanizedversion thatretained potency for theneutralization of DENV-2 and did not enhance the viral infection. The DB32-6 showed therapeutic efficacy against mortality induced by differentstrainsofDENV-2intwomousemodelseveninpost-exposuretrials. Conclusions/Significance:Weusednovelepitopemappingstrategies,bycombiningphagedisplaywithVLPs,toidentify theimportantA-strandepitopeswithstrong neutralizingactivity.Thisstudyintro